Organizations such as pharmaceutical companies are increasingly turning to solid-state nuclear magnetic resonance spectroscopy (SSNMR) analysis, for example in testing low dose active pharmaceutical (API) formulations such as in blends and drug products. The low dose of the API results in long (24 hr+) experimental times, severely limiting throughput on a single spectrometer using a traditional SSNMR probe. This is because in conventional nuclear magnetic resonance (NMR) magnets solid-state NMR analysis must be done one sample at a time, and because of long delays between pulses, may require lengthy spectrum acquisition times. For most solid samples, less than one percent of the time in the magnetic field is spent on data acquisition. The rest of the time is spent waiting for the spin populations to return to their equilibrium value. During this time the sample must remain in a large static magnetic field, but is not required to be in a homogenous magnetic field. Moreover, a typical 400 MHz SSNMR instrument may cost around $600K, whereas a higher field instrument, such as an 800 MHz or 900 MHz spectrometer, can range from $2-5 MM.
Thus, conventional SSNMR is inherently an expensive, low throughput technique for the analysis of compounds, and because of the cost of current NMR machinery single sample analysis is undesirable. Any method that increases either the signal to noise ratio (SNR) and/or the throughput (number of samples analyzed per unit time) would be extremely beneficial. As alternatives to allow multi-sample analyses, 2 module and 4 module NMR probes have been developed (see U.S. Pat. Nos. 6,937,020 and 7,626,391 to Munson et al., the entirety of each of which is incorporated herein by reference) to attempt to maximize utilization of this expensive tool. While effective for their intended purposes, these probes disadvantageously require movement within the NMR magnet and/or provide insufficient isolation between samples being analyzed.
Specifically, three primary disadvantages have been identified for conventional NMR probe technology. The first is that the probe is constantly moving up and down in the magnet, which could be perceived negatively. Second, eddy currents caused by moving the probe up and down in the bore of the magnet were found to be problematic at high fields (>600 MHz), limiting the benefits of such probes to long-relaxing samples that allowed the eddy currents to die down. Finally, most high field NMR experiments are performed on protein samples, which typically have a relatively short (˜1-3 s) recycle delay between repetitions. These samples do not benefit from such probes, and made this technology less interesting to solid-state NMR spectroscopists.
As an example, two-module multiple-sample probes (see U.S. Pat. No. 6,937,020) are known providing magic-angle spinning (MAS) modules that are 25 mm apart, although there is the capacity to change the distance if necessary. There is also the capability of tuning from the base of the probe, which is located outside the bore of the magnet. After extensive experimental testing it was observed that: 1) The signal-to-noise ratio for X nuclei such as 13C is equivalent to that of a traditional λ/4 commercial probe design; 2) Proton power was comparable to a traditional coaxial probe design.
However, RF “crosstalk” between the two modules was observed. FIG. 1 shows 13C CPMAS NMR spectra of 3-methylglutaric acid (MGA) obtained using the two-module probe of U.S. Pat. No. 6,937,020. As can be seen therein, isolation of the proton signal between the two sides of the probe was a challenge, resulting in the saturation of signal from one of the modules (D). The prior art solution was a passive feedback system (similar to an op-amp feedback mechanism). However, this approach could not be scaled to more than two MAS modules.
There is thus a need in the art for multi-sample NMR probes which allow acquisition of multiple spectra for improved throughput, without the disadvantages of prior art systems as described above. To satisfy this need in the art, a multi-sample probe is disclosed comprising multiple MAS modules. The described probe provides isolation of the entire RF circuit of each MAS module of the probe. Advantageously, the probe allows simultaneous SSNMR analysis of multiple samples, without requiring probe movement within the NMR magnetic field during sample acquisition.